Chemotherapy remains the standard first-line treatment for many cancers, including lung cancer, the leading cause of cancer deaths responsible for approximately 160,000 deaths every year in the United States alone. However, the benefits of current chemotherapy are very limited due to intrinsic and acquired resistance of cancer cells. The long-term goal of our research is to understand the mechanisms underlying tumorigenesis and chemoresistance, and to translate this understanding into novel approaches to improve cancer cure rates by establishing new effective therapies and/or priming cancer cells to respond to current therapeutic drugs. To this end, we have recently identified PDLIM2, a ubiquitously expressed PDZ-LIM domain-containing protein with the highest level in lungs, as a suppressor of lung cancer and several other cancer types such as adult T-cell leukemia/lymphoma (ATL), breast, and colon cancers. We find that the expression of PDLIM2 is epigenetically repressed in these cancer cells, and that PDLIM2 reconstitution prevents their tumorigenicity. Moreover, PDLIM2 deficiency predisposes mice to spontaneous and induced cancers, particularly lung cancer. Notably, the repression of PDLIM2 expression is associated with the chemotherapy resistance of lung cancer, and PDLIM2 re-induction is required for the epigenetic drug 5-aza-dC to induce growth inhibition and response to the chemotherapeutic drug carboplatin in multidrug resistant lung cancer cells. Mechanistic studies indicate that PDLIM2 functions as a ubiquitin E3 ligase to selectively degrade nuclear (activated) NF-?B RelA (also known as p65), a transcription factor that has been suggested to play a causative role in tumorigenesis and therapeutic resistance of multiple human cancers, including ATL, breast, colon and lung. Based on these innovative findings, we hypothesize that PDLIM2 repression leads to constitutive NF?B activation, which in turn contributes to cancer pathogenesis and therapy resistance. In this application, we aim to (1) determine the molecular mechanisms by which PDLIM2 expression is repressed in lung cancer; (2) elucidate the mechanistic role of PDLIM2 in lung cancer development; and (3) examine the role and mechanisms of PDLIM2 in lung cancer chemosensitivity and therapy. These studies are innovative and significant, because they will greatly increase our understanding of the tumorigenesis and chemoresistance of lung cancer, and may form a novel class of PDLIM2-based epigenetic approaches as a primary or adjuvant therapy for lung cancer prevention and treatment. In particular, clinical trials show that it is impractical to block NF-?B activation for cancer therapy using 'classical' NF-?B inhibitors because of the importance of NF-?B in human physiology. However, PDLIM2 prevents pathogenic but not physiological activation of NF-?B by terminating NF-?B activation. Consistently, PDLIM2 expression, although repressed in cancer cells, is high under physiological conditions. Thus, PDLIM2-based therapies will effectively alleviate NF-?B-mediated tumorigenesis and chemoresistance while keeping the physiological functions of NF-?B, such as immune responses, intact in patients. Moreover, it is feasible to target PDLIM2 for cancer therapy because our studies show that the repression of PDLIM2 expression in cancer cells is pharmacologically reversible.